Research report
Effect of chronic nicotine on brain stimulation reward. II. An escalating dose regimen

https://doi.org/10.1016/S0166-4328(98)00013-8Get rights and content

Abstract

This study examined whether repeated nicotine injections, using an escalating dose regimen, would produce brain stimulation reward facilitation indicative of a strong rewarding action. Male, Long-Evans rats with lateral hypothalamic stimulating electrodes were injected daily with escalating doses of nicotine bitartrate across 5-day cycles: 0.5, 1, and 2 mg/kg/day (dose expressed as freebase weight) were administered subcutaneously (s.c.) in consecutive 5-day cycles. Nicotine lowered thresholds across the first two 5-day cycles (i.e. 0.5 and 1 mg/kg/day doses), but thresholds returned to baseline levels during the last 5-day cycle (i.e. 2 mg/kg/day). The maximum threshold lowering produced by nicotine was similar to that previously reported for acute and chronic nicotine and for mild stimulants with a low addiction liability (i.e. caffeine and pseudoephedrine). Forty-eight h after terminating the nicotine injection regimen, thresholds were elevated revealing a nicotine withdrawal reaction. However, the high nicotine dose used during the last 5-day cycle is probably not pharmacologically relevant, thus making the significance of the withdrawal effect unclear. Overall, this study suggests that even under chronic administration using escalating doses, nicotine's profile in this animal model is that of a substance with a low addiction liability.

Introduction

The effect of a compound on brain stimulation reward (BSR) provides a measure of the compound's action on an important brain reward system. Both opiates and psychomotor stimulants activate the neural pathway that is activated by lateral hypothalamic brain stimulation 3, 27, 28. This pharmacological activation enhances the rewarding impact of the electrical stimulation and produces BSR facilitation (e.g. stimulation-threshold lowering). BSR has been proposed as a model of the hedonic impact of a compound and is thought to reflect the compound's intrinsic rewarding effect and therefore its potential addiction liability (11, 22; see also [4]). This model has both face validity and considerable empirical support. Drugs that enhance the rewarding effects of electrical brain stimulation are generally highly addictive, and drugs that are not addictive usually fail to enhance BSR.

Nicotine has been shown to facilitate BSR 1, 9, 17, 18, 21, and these data are consistent with the proposed rewarding action of nicotine. However, recent work [5]supports an earlier suggestion [2]that quantitative aspects of a compound's effect on BSR are important in estimating its potential addiction liability. Some compounds which reliably facilitate BSR have a low addiction liability (e.g., nalorphine; [23]). Therefore, the magnitude of the facilitation effect must be considered when using BSR to assess a substance's potential addiction liability.

To distinguish the effects of compounds with high and low addiction liabilities, the facilitation produced by highly addictive compounds (e.g. cocaine) must be compared not only with inert substances (e.g. physiological saline) but with mildly psychoactive compounds that have a low addiction liability (e.g. pseudoephedrine). This avoids the problem of confusing substances that may have marginal rewarding effects with substances that have the potent rewarding effects characteristic of addictive drugs. Previous work has shown that nicotine produces BSR facilitation with the response profile of a compound with a low addiction liability [5], even when chronically administered 1, 6. This facilitation effect is quantitatively distinguishable from that obtained with prototypic addictive drugs. The possibility remains, however, that repeated, high-dose nicotine administration may enhance nicotine's potential rewarding action, and this enhanced rewarding impact may produce facilitation similar to that seen with prototypic addictive drugs. This study examined the effect of chronic nicotine on BSR using an escalating dose procedure designed to test the effect of repeated, high-dose nicotine administration.

Initial tobacco use by humans can produce aversive effects but tolerance quickly develops permitting continued, increasing tobacco use ([26]; see also [20]). Increasing tobacco use increases nicotine administration and may produce a strong rewarding action not present with initial, low-level tobacco use. Similarly, initial nicotine administration can produce apparent malaise in laboratory animals as shown by the development of conditioned taste aversions (e.g. 10, 12) and by the disruption of operant behavior and locomotor activity. Tolerance quickly develops to the behaviorally disruptive effects of nicotine in laboratory animals (e.g. 6, 25). One strategy to investigate the maximum facilitatory action of nicotine is to mimic the escalating nicotine doses which occur during the acquisition of smoking behavior in humans. Nicotine doses are systematically increased, with repeated administration of each dose permitting the development of tolerance to nicotine's aversive effects. This allows testing larger nicotine doses with minimal disruptive effects. The initial nicotine dose selected for this study produces maximum BSR facilitation during acute administration. The nicotine dose then increases every 5 days until toxic reactions are noted.

Section snippets

Subjects

Male, Long-Evans rats (Harlan Sprague-Dawley, Altamont, NY), weighting 225–275 g at the time of surgery, were implanted with monopolar stimulating electrodes aimed at the lateral hypothalamic level of the medial forebrain bundle. With the upper incisor bar 3.3 mm below the interaural plane, the coordinates were posterior 3.3 from bregma, lateral ±1.8 from the midline mm, and 8.4 mm below dura. Electrodes were fabricated from 0.25 mm stainless steel wire insulated with Formvar except at the

Results

Fig. 1 shows the threshold-lowering effect of nicotine across the 15-day escalating dose regimen. Daily nicotine injections lowered thresholds across the first two 5-day cycles. The threshold-lowering effect of the 0.5 mg/kg/day and the 1 mg/kg/day nicotine doses were essentially the same. When the nicotine dose was increased to 2 mg/kg/day during the last 5-day cycle, thresholds unexpectedly returned to baseline levels. Animals administered physiological saline daily showed little variation

Discussion

The objective of the present study was to determine the maximum facilitation of BSR that can be produced by high-dose nicotine administration. The experimental strategy was to increase the nicotine dose across successive 5-day cycles. Each dose of nicotine was repeated for several days to permit the development of tolerance to the disruptive effect of nicotine at each dose level. This protocol was designed to mimic the increasing nicotine doses experienced during the acquisition of smoking

Acknowledgements

Matt Morris is thanked for assistance in behavioral testing. Data reported in this paper are from the Nicotine Evaluation Program supported by a grant from the Philip Morris Research Center (Richmond, VA). The opinions expressed herein are those of the authors and not necessarily those of the sponsor.

References (28)

  • Bozarth MA, Pudiak CM, KuoLee R. Effect of chronic nicotine on brain stimulation reward. I. Effect of single daily...
  • M.A. Bozarth et al.

    A threshold tracking procedure for studying brain stimulation reward

    Soc Neurosci Abstr

    (1990)
  • S.R. Grady et al.

    Desensitization of nicotine-stimulated [3H]dopamine release from mouse striatal synaptosomes

    J Neurochem

    (1994)
  • C. Kornetsky et al.

    Intracranial self-stimulation thresholds: A model for the hedonic effects of drugs of abuse

    Arch Gen Psychiatr

    (1979)
  • Cited by (21)

    • Effects of nicotine conditioning history on alcohol and methamphetamine self-administration in rats

      2019, Pharmacology Biochemistry and Behavior
      Citation Excerpt :

      As such, given an increased reward value, female rats required less methamphetamine overall. Similar findings have been observed in studies of brain stimulation in which nicotine decreases frequency threshold for reinforcement (Bozarth et al., 1998a, 1998b; Ivanova and Greenshaw, 1997). Alternatively, the reduction in self-administration in the females could instead be interpreted as decreased reinforcement efficacy of methamphetamine, perhaps due to enhanced anxiogenic effects of methamphetamine (Beirami et al., 2017; Schutova et al., 2009).

    • Effects of nicotine-containing and “nicotine-free” e-cigarette refill liquids on intracranial self-stimulation in rats

      2018, Drug and Alcohol Dependence
      Citation Excerpt :

      This lack of translation across behavioral models may reflect differences in route of administration, nicotine dose, or contingency (see LeSage et al., 2016). In addition, tolerance develops rapidly to nicotine’s aversive/anhedonic effects, but not to its reinforcement-enhancing effects, upon repeated administration (Bauco and Wise, 1994; Bozarth et al., 1998; Freitas et al., 2016). This may limit the impact of an attenuation of nicotine’s aversive/anhedonic effects in drug SA procedures, which necessarily involve repeated administration.

    • Neurological Effects of Nicotine, Tobacco, and Particulate Matter

      2016, Neuropathology of Drug Addictions and Substance Misuse
    • Neurological Effects of Nicotine, Tobacco, and Particulate Matter

      2016, Neuropathology of Drug Addictions and Substance Misuse Volume 1: Foundations of Understanding, Tobacco, Alcohol, Cannabinoids and Opioids
    • Translational research in addiction: Toward a framework for the development of novel therapeutics

      2011, Biochemical Pharmacology
      Citation Excerpt :

      Most frequently, researchers utilize morphine pellets or nicotine-filled subcutaneous osmotic minipumps, although repeated acute injections of drug have also been used. Rather than antagonist administration, cessation of chronic administration of nicotine [123,124] or morphine [125] resulted in attenuation of BSR. The attenuation of BSR is interpreted as a measure of anhedonia [132].

    View all citing articles on Scopus
    View full text